Deciphering the Glycolipid Code of Alzheimer's and Parkinson's Amyloid Proteins Allowed the Creation of a Universal Ganglioside-Binding Peptide

Abstract

A broad range of microbial and amyloid proteins interact with cell surface glycolipids which behave as infectivity and/or toxicity cofactors in human pathologies. Here we have deciphered the biochemical code that determines the glycolipid-binding specificity of two major amyloid proteins, Alzheimer's β-amyloid peptide (Aβ) and Parkinson's disease associated protein α-synuclein. We showed that both proteins interact with selected glycolipids through a common loop-shaped motif exhibiting little sequence homology. This 12-residue domain corresponded to fragments 34-45 of α-synuclein and 5-16 of Aβ. By modulating the amino acid sequence of α-synuclein at only two positions in which we introduced a pair of histidine residues found in Aβ, we created a chimeric α-synuclein/Aβ peptide with extended ganglioside-binding properties. This chimeric peptide retained the property of α-synuclein to recognize GM3, and acquired the capacity to recognize GM1 (an Aβ-inherited characteristic). Free histidine (but not tryptophan or asparagine) and Zn2+ (but not Na+) prevented this interaction, confirming the key role of His-13 and His-14 in ganglioside binding. Molecular dynamics studies suggested that the chimeric peptide recognized cholesterol-constrained conformers of GM1, including typical chalice-shaped dimers, that are representative of the condensed cholesterol-ganglioside complexes found in lipid raft domains of the plasma membrane of neural cells. Correspondingly, the peptide had a particular affinity for raft-like membranes containing both GM1 and cholesterol. The chimeric peptide also interacted with several other gangliosides, including major brain gangliosides (GM4, GD1a, GD1b, and GT1b) but not with neutral glycolipids such as GlcCer, LacCer or asialo-GM1. It could inhibit the binding of Aβ1-42 onto neural SH-SY5Y cells and did not induce toxicity in these cells. In conclusion, deciphering the glycolipid code of amyloid proteins allowed us to create a universal ganglioside-binding peptide of only 12-residues with potential therapeutic applications in infectious and neurodegenerative diseases that involve cell surface gangliosides as receptors.

1-Methyl-4-Phenylpyridinium-Induced Death of Differentiated SH-SY5Y Neurons Is Potentiated by Cholesterol

“…One of the major pathogenic markers of PD, α-synuclein monomers is also shown to undergo lipid raft-dependent internalization in SH-SY5Y-glial co-cultures, heightened the relevance of the present investigation [18]. Furthermore, molecular dynamics studies evidenced binding of α-synuclein in its chimeric form, which are condensed cholesterol-ganglioside complexes found in lipid raft domains of the plasma membrane of neurons [19]. Above all, our laboratory has been using this cell line for investigating neurodegenerative disease biology for the past several years [13, 15, 20, 21].…”

Protein–Lipid Interactions in the Brain

“…70 Among the most notable achievements of this algorithm, one could mention the characterization of the SBD identified in a putative adhesion of Helicobacter pylori. 73 Single mutations in synthetic SBDs at positions predicted to be important for sphingolipid recognition systematically abrogated or strongly decreased sphingolipid binding. This synthetic SBD recapitulated the glycosphingolipid binding properties of the whole bacterium, especially the selective recognition of LacCer and the lack of interaction with Gb 3 .…”

Common Mechanisms in Neurodegenerative Diseases

“…Interestingly, the SBD is close to an acidic Glu residue that is mutated into a basic lysine in inherited forms of Alzheimer's (Glu-22), Creutzfeldt-Jakob (Glu-200), and Parkinson's (Glu-46) diseases. 51,61 The possibility to generate broadly neutralizing antioligomer antibodies by immunizing with SBD peptides is currently under evaluation. The SBD of Ab, PrP, and a-synuclein is a common structural motif recognized by several glycolipids, including gangliosides and GalCer.…”